Role of lipid rafts and phosphoinositides in E. histolytica virulence

脂筏和磷酸肌醇在溶组织内阿米巴毒力中的作用

基本信息

批准号：
7884312
负责人：
LESLY A TEMESVARI
金额：
$ 21.63万
依托单位：
CLEMSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-02-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7884312
关键词：
1-Phosphatidylinositol 3-Kinase Acetylgalactosamine Actins Address Adhesions Amebiasis Amebic colitis Biological Biology Biosensor Bioterrorism Categories Cell Adhesion Molecules Cell Line Cell membrane Cells Cellular biology Cessation of life Cholesterol Cyst Cytoskeleton DNA Sequence Rearrangement Data Density Gradient Centrifugation Detection Detergents Developing Countries Disease Dominant-Negative Mutation Drug Design Entamoeba histolytica Environment Enzymes Epithelium Epitopes Erythrophagocytosis Eukaryota Eukaryotic Cell Event Funding Gal-GalNAc Galactose Gene Expression Genetic Guanosine Triphosphate Phosphohydrolases Homologous Gene Human Infection Lead Lectin Ligand Binding Lipid Binding Lipids Liver Abscess Membrane Membrane Microdomains Morbidity - disease rate Nature Oral Organ Parasites Parasitic Diseases Pathogenicity Phagocytosis Phosphatidylinositols Phosphoric Monoester Hydrolases Play Proteins Public Health Recruitment Activity Regulation Research Personnel Resistance Role Running Signal Pathway Signal Transduction Signaling Molecule Sphingolipids Sucrose System Testing Therapeutic Time Vaccines Vesicle Virulence base extracellular innovation insight macromolecule mutant novel pathogen phosphatidylinositol 3-phosphate prevent programs protein function rab GTP-Binding Proteins tensin trafficking

项目摘要

DESCRIPTION (provided by applicant): Entamoeba histolytica is the causative agent of amoebic dysentery and liver abscess. It ranks third as a worldwide cause of morbidity and has been classified as a Category B bioterrorism agent. Therefore, there is elevated priority to understand the biology of and develop innovative detection and therapeutic strategies for this pathogen. E. histolytica trophozoites will encounter a variety of host cells and macromolecules during infection. It is postulated that these extracellular components trigger signaling cascades in the parasite that lead to changes in virulence. With the rate at which the components of signaling pathways are being discovered in E. histolytica, the new challenge is to understand the temporal and spatial regulation of signaling events in these cells. In other eukaryotes, lipid rafts (cholesterol- and sphingolipid-rich plasma membrane domains), along with the actin cytoskeleton, and phosphoinositides (Pis), compartmentalize signaling events in the plasma membrane. Recently, E. histolytica cells were shown to possess raft-like plasma membrane domains. The co-localization of rafts with an important signaling/adhesion molecule, the galactose/N-acetylgalactosamine (Gal/GalNAc) lectin, suggests that rafts may also participate in signaling in E. histolytica. In the proposed studies, the biological role of E. histolytica lipid rafts, as well as of several Pis, will be explored. In the first Aim, the relationship between rafts and actin, and their role in virulence will be examined. In the second Aim, the connection between lipid rafts, vesicle trafficking, and actin will be assessed utilizing genetic approaches with mutants in which these cellular components are uncoupled. Finally, in the third Aim, the role of Pis in parasite virulence functions will be examined. This will be achieved by examining the function of PI 3-kinase and PTEN phosphatase, enzymes with complimentary roles in Pi- based signaling. Since vesicle trafficking, actin cytoskeletal rearrangements and signaling likely regulate virulence; these studies will contribute significantly to understanding the pathogenicity of E. histolytica. Public Health Description: Entamoeba histolytica is the causitive agent of amoebic dysentery and liver abscess and ranks third in the world for deaths due to parasitic disease. Since it is also classified as a bioterrorism agent, there is elevated priority to understand its virulence. The proposed studies will examine signaling pathways that are activated during parasite-host interaction. Since signaling likely regulates virulence, these studies will contribute significantly to understanding the biology of E. histolytica.

描述（由申请人提供）：Entamoeba Histolictica是Amoebic痢疾和肝脓肿的病因。它排名第三，是全球发病率的原因，并已被归类为B类生物恐怖剂。因此，优先考虑并发展了该病原体的创新检测和治疗策略的优先级。 E. histoltica滋养体将在感染过程中遇到各种宿主细胞和大分子。据推测，这些细胞外成分触发寄生虫的信号传导级联反应，导致毒力变化。随着在E. histolictica中发现信号通路的成分的速率，新的挑战是了解这些细胞中信号事件的时间和空间调节。在其他真核生物中，脂质筏（胆固醇和富含鞘脂的质膜结构域）以及肌动蛋白的细胞骨架以及磷酸肌膜（PIS），在质膜膜中的信号事件分隔化。最近，溶组织溶解菌细胞具有筏样质膜结构域。与重要的信号传导/粘附分子，半乳糖/N-乙酰乳糖胺（GAL/GALNAC）凝集素的筏共定位，表明筏子也可能参与溶组织溶解性菌群中的信号传导。在拟议的研究中，将探索溶解大肠杆菌脂质筏的生物学作用以及几个PI。在第一个目标中，将检查筏与肌动蛋白之间的关系，以及它们在毒力中的作用。在第二个目的中，将通过使用突变体的遗传方法来评估脂质筏，囊泡运输和肌动蛋白之间的联系，其中这些细胞成分是未偶联的。最后，在第三个目标中，将检查PI在寄生虫毒力功能中的作用。这将通过检查PI 3-激酶和PTEN磷酸酶的功能，即在基于PI的信号传导中具有免费作用的酶。由于囊泡运输，肌动蛋白细胞骨架重排和信号传导可能调节毒力；这些研究将有助于理解组织溶液性大肠杆菌的致病性。公共卫生描述：Entamoeba Histolictica是Amoebic痢疾和肝脓肿的因果因素，由于寄生虫病而死亡，在世界上排名第三。由于它也被归类为生物恐怖剂，因此优先考虑其毒力。拟议的研究将检查在寄生虫宿主相互作用期间激活的信号通路。由于信号传导可能调节毒力，因此这些研究将有助于理解溶血性大肠杆菌的生物学。